Research ArticleLiver disease

Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis

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Science Translational Medicine  27 Nov 2019:
Vol. 11, Issue 520, eaav9701
DOI: 10.1126/scitranslmed.aav9701

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A pill a day keeps liver fat away

Nonalcoholic fatty liver diseases can progress to liver failure but currently lack approved treatments. Amin et al. tested the therapeutic efficacy of a small-molecule inhibitor of diacylglycerol acyltransferase 2 (DGAT2; responsible for hepatic triglyceride production) in rodent models of nonalcoholic steatohepatitis and found that PF-06427878 improved liver steatosis and function. Two phase 1 clinical trials in healthy humans showed improved markers of liver function at the highest dose administered. One of the clinical trials measured liver fat and demonstrated its reduction in healthy participants on the highest dose. PF-06427878 may be a candidate to treat conditions related to fatty liver in humans.

Abstract

Nonalcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatocyte triglycerides, the synthesis of which is catalyzed by diacylglycerol acyltransferases (DGATs). Here, we investigate DGAT2 as a potential therapeutic target using an orally administered, selective DGAT2 inhibitor, PF-06427878. Treatment with PF-06427878 resulted in the reduction of hepatic and circulating plasma triglyceride concentrations and decreased lipogenic gene expression in rats maintained on a Western-type diet. In a mouse model of NASH, histological improvements in steatosis, ballooning, and fibrosis were evident in the livers of animals receiving PF-06427878 compared with mice treated with vehicle alone. We extended these nonclinical studies to two phase 1 studies in humans [NCT02855177 (n = 24) and NCT02391623 (n = 39; n = 38 completed)] and observed that PF-06427878 was well tolerated and influenced markers of liver function (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin) in healthy adults, with statistically significant reductions from baseline at day 14 in participants treated with PF-06427878 1500 milligrams per day (P < 0.05). Moreover, magnetic resonance imaging using proton density fat fraction showed that PF-06427878 1500 milligrams per day reduced hepatic steatosis in healthy adult participants. Our findings highlight DGAT2 inhibition by a small, potent, selective compound as a potential therapeutic approach for the treatment of NASH.

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